The major cause of morbidity and mortality in sickle cell disease (SCO) is tissue ischemia and infarction due to vascular occlusion that results in progressive organ damage. It is unclear whether the enhanced procoagulant or inflammatory activity observed in SCO directly contributes to the pathogenesis of sickle cell vaso-occlusive disease or merely reflects vascular injury caused by the sickle erythrocyte. We hypothesize that sickle erythrocytes initially injure the endothelium, inducing both a proinflammatory and procoagulant phenotype; we propose that the increased inflammation contributes to reversible vascular stasis while the coagulant pathway contributes to the complete stoppage of blood flow and tissue infarction. The strong interrelationships between the inflammatory and hemostatic pathways set up a vicious cycle that further propagates this process. Therefore, the Specific Aims for this project are to 1) Characterize the effects of thrombin generation and fibrin formation on the cycle of HbS-induced endothelial injury, inflammation and vascular congestion, 2) Define the role of the tissue factor pathway in the evolution of sickle cell-induced vascular pathology, and 3) Study the effect of modulation of the protein C/thrombomodulin pathway on the evolution of HbS-induced organ pathology. We will induce SCO into mice with genetic alterations of specific components of the coagulation and coagulant signaling pathways using hematopoietic stem cell transplantation and test the effect on measures of inflammation and endothelial injury. We will also examine the effect of pharmacologic and genetic anticoagulant therapy in SCO mice as well as hypoxia-reoxygenation-treated SCO mice. Finally, we will study the role of thrombosis and inflammation on sickle red cell adhesion in vivo. We anticipate that these studies will clarify the interrelated roles of the coagulation system, vascular injury and inflammation in the evolution of sickle cell-induced vascular pathology. Additionally, these studies will provide insights into the value of targeted anticoagulant/anti-inflammatory therapies for the treatment and prevention of SCD vascular pathology.